Alpha-Synuclein (alpha-S) is a 140 amino acid, intrinsically disordered protein that adopts an amphipathic alpha-helical structure upon binding the membrane. Alpha-S is the major proteinaceous component of insoluble fibrillar Lewy bodies, a hallmark of Parkinson's disease (PD). The precise roles of both native and pathological forms of alpha-S remain unclear. However, the interaction of alpha-S with cellular membranes is now thought to be critical to its native function, and potentially to its role in PD as well. We propos a series of Low-Angle X-ray Scattering (LAXS) experiments and molecular dynamics (MD) simulations to more fully understand the membrane remodeling effects of native alpha-S. We will be primarily focused on the role of lipid composition and bilayer curvature. In particular, we propose the following two specific aims, each of which will be carried out in parallel: 1) Determine how alpha-S remodels membranes when bound to both monolayer leaflets. 2) Determine how alpha-S remodels membranes when bound to only one leaflet, modeling its physiological action on synaptic vesicles. Each of these aims will test our hypothesis that the intrinsic, natural curvature of alpha-S dictates its capacity to remodel and stabilize membranes, in particular those that are highly curved (like synaptic vesicles). PUBLIC HEALTH RELEVANCE: The membrane protein alpha-synuclein has been implicated as playing a central role in both sporadic and familial forms of Parkinson's disease, the most common neurodegenerative movement disorder. Through developing a biophysical understanding of alpha-synuclein induced membrane remodeling, we will gain insight into the native function of alpha--synuclein, and in turn be well positioned to begin to understand its role in the disease.